Trends in Molecular Medicine
S-nitrosylation in health and disease
Section snippets
Molecular mechanism versus integrated (patho)physiological model
The distinguishing feature of S-nitrosylation compared with other post-translational protein modifications (e.g. phosphorylation and glycosylation) is that no single or even general reaction applies; the reaction mechanism (molecular-level behavior) is largely a function of the peptide or protein being modified. Moreover, the mechanism can change as a function of the concentration of reactants and the redox state of the system. Thus, in any discussion of SNO biology (integrated system), the
S-nitrosylation by NOS
Although NOS activity is associated with many physiological responses, few of the crucial protein targets are known and the molecular details are poorly defined. However, all isoforms of NOS, as well as all physiological stimuli that activate NOSs, lead to nitrosative chemistry and thus to S-nitrosylation. In vivo imaging of cells using the fluorogenic NO+ scavenger, 4,5-diaminofluorescein, has revealed that NOS localization and activation are spatially coincident and co-temporal with
Coupling of blood flow and breathing
Endothelium-dependent relaxation of blood vessels regulates blood flow in response to shear stress, and is mediated through both cGMP production and S-nitrosylaton of key ion channels [3]. By contrast, red blood cells (RBCs) mediate hypoxic vasodilation: they act as a vehicle for O2-regulated delivery of NO signals, in the form of SNOs (hypoxic vasodilation is not blocked by NOS inhibitors). In particular, human hemoglobin (Hb) has been shown to bind and convert NO to bioactive nitrosothiol (at
Tuning of blood pressure, blood clotting and muscle contractility
In an aqueous environment, reaction of NO with dioxygen proceeds via dinitrogen trioxide (N2O3), a potent nitrosating agent. N2O3 can nitrosate thiols, implicating this species in protein S-nitrosylation under aerobic conditions. Auto-oxidation is slow on a physiological timescale, but because NO and O2 have up to ten times greater solubilities in hydrophobic environments than in water [38], their partitioning within biological membranes and hydrophobic compartments is predicted to accelerate N2
Sensing and signaling: tactile stimuli, hypoxia and nitrosative stress
Transnitros(yl)ation is invoked in the physiological responses to small-molecule SNOs that are not reproduced by NO itself. Thus, this mechanism is implicated in the effects of somatosensory afferent stimulation (which produces CysGlyNO [46]) and in the role of GSNO (or CysNO/CysGlyNO) in triggering hypoxic ventilation [26]. Transnitrosylation is arguably the only chemical reaction involving NO that has been shown by stringent genetic criteria to occur in vivo. Mouse hepatocytes lacking GSNO
Physiology (blood and gut) and pathology (ischemia and asthma)
Resident nitrite (NO2−), acquired through dietary uptake and NOS activity, might serve as an alternative source of NO bioactivity and S-nitrosylation in low pH conditions, such as in the stomach and the asthmatic airway [56]. This reaction mechanism could have evolved to protect against microbial pathogens encountered in the gut, and to recycle NO bioactivity. NO synthesis from NO2− is also predicted to increase 100-fold in ischemic tissue (pH 5.5), compared with normally perfused tissue (pH
Plasma SNOs, hemostasis and hypercholesterolemia
In the plasma, copper-mediated catalysis of S-nitrosylation might be a relevant mechanism for generating bioactive SNOs. Copper binds BSA at Cys34 and catalyzes S-nitrosylation of this residue by NO [59]. Copper either oxidizes NO· to NO+ or generates a thiyl-radical intermediate that subsequently reacts with NO· directly (Table 3). It is possible that at physiological plasma NO concentrations (perhaps 1–10 nM), metal catalysis dominates the more widely studied auto-oxidation and
Elevated nitrosothiols (nitrosative stress)
Excessive SNO, either systemic or local, has been detected by a variety of techniques in patients with inflammatory and autoimmune diseases. However, the link between increased SNO synthesis and the development of pathology requires further study in each case. Indeed, a protective or compensatory role of SNOs is possible, including antimicrobial functions and the diversion of toxic NO-related species to a more inert form, as suggested by the accumulation of antimicrobial SNOs in the blood of
Depletion of nitrosothiols
The mechanisms by which nitrosothiols are degraded are of key importance to the understanding of S-nitrosylation in health and disease. The release of SNO-metabolizing enzymes and other transition-metal-containing proteins from injured cells, during preparatory techniques or disease, might contribute to observed variances in SNO levels (physiological variations as well as experimental artefacts, notwithstanding other differences in methods, sample processing and techniques). In particular,
SNO therapy
Inhaled NO gas (iNO) provides important therapeutic benefits to babies with persistent pulmonary hypertension of the newborn, although concerns about toxicity remain. However, iNO therapy is harder to rationalize in diseases such as asthma and adult respiratory distress syndrome (ARDS), which present with clinical signs of NO deficiency (airway constriction and V/Q mismatching), but are actually characterized by elevated NO production. In addition, the deficiency of NO bioactivity that promotes
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